Quaternary ammonium compounds of bis-tertiary aminoalkoxy alkanes



Patented July 6, 1954 UNITED STATES ATENT OFFICE QUATERNARY AMMONIUMGOMPOUNDS OF BIS-TERTIARY AMINOALKOXY ALKANES Emil Girod, Riehen, nearBasel, Switzerland, as-

signor to J. R. Geigy A. G., Basel, Switzerland,

a Swiss firm No Drawing. Application November 28, 1950, Serial No.198,024

Claims priority, application Switzerland December 7, 1949 8 Claims. 1This process concerns the production of bistertiary aminoalkoxy alkanesand their quaternary ammonium halides.

According to the present invention new bisare provided wherein:

R represents the same or different alkyl radicals with 1-4 C atoms,particularly a methyl or an ethyl radical or else two R radicalstogether a I with the N atom represent a saturated heterocyclic radicalwith 5-6 members such as a pyrrollidino-, piperidino-, 2-methylpiperidino or morpholino ralical,

Hal represents chlorine, bromine or iodine, m and m represent integersfrom 2-4, and n represents an integer of at least 2 and m, n and intogether represent a sum of at least 8.

In principle, the new compounds can be made up e. g. frpm glycols of theformula and secondary or tertiary amines by methods known per se. Thus,the bis-tertiary bases can be produced for example by reaction ofbis-halogen alkoxyalkanes of the general formula:

III"

with secondary aliphatic or heterocyclic amines of the formula:

In the above and all further formulae R, Hal, m, n and m have themeanings given above.

The bis-halogen akoxyalkanes of the general Formula III such as forexample 1.2-bis-(6- bromobutoxy) -ethane can be obtained by reaction ofthe corresponding biS-(ca-hYdI'OXYEtIkOXY) alkanes with phosphorushalides according to Ziegler and Holl Ann. 528, 152 (1937).

The bis-tertiary bis-aminoalkoxy alkanes can (o zoo-294.7)

also be obtained by reaction of a,w-alkane-diols of the general formula:

most advantageously in the form of their metal compounds (i. e.alcoholates) With 2 mols of tertiary aminoalkoxy halides of the generalformula:

This process is suitable for instance for the production of bis-tertiarybis-(' -aminopropoxy) alkanes.

It is also possible to react a,w-dihalogen alkanes of the generalformula:

with 2 mols of tertiary aminoalcohols of the general formula:

Their alcoholates can be reacted with, e. g. ,3- chloroethylor 'ybromopropyl dimethylamine, -methyl-et-hylamine, -methylpropylamine,methyl-butylamine, -methyl-isobutylamine, -di ethylamine, -ethylpropylamine, -ethy1butylamine, -ethylisobutylamine, -dipropylamine,-propyl-butylamine, -propylisobutylamine, -dibutylamine,-butyl-isobutylamine, -di-isobutylamine, -methyl-isopropylamine,-methyl-second ary butylamine; N-(fi-chlorethyl)-orN-(vbromopropyl)-pyrrolidine, -piperidine, -2-methyl-pip'eridine,-morpholine.

Also the bis-tertiary bis-aminoalkoxy alkanes can be produced from adi-primary diamine by tetra-alkylation. This process particularly comesinto question when the bis-primary di amines are easily accessible forinstance by adding 1 mol of an a,w-diol to 2 mole of acrylonitrile andthen reduction of the bis- -aminopropoxy) alkanes as described in D. R.P. 734,475.

The quaternary ammonium compounds can be produced by two methodsthroughthe reaction of tertiary amines with halogen compounds. Either atleast 2 mols of alkyl halides of the general formula:

R-Hal are reacted with a bis-tertiarybis-aminoalkoxy alkane of thegeneral formula:

R =R 1 or at least 2 mols of tertiary amines of the general f ormula:

are reacted with a bis-halogen alkoxyalkane oi the general formula:

On using methyl iodide, the tertiary amines generally take up thehalogen compounds at room temperature and under liberation of heat, butin most cases the reaction mixture must be heated to obtain a completereaction. The reactions can be performed either in the presence orabsence of suitable solvents. As such acetone, butanone, acetic ester,benzene, toluene, xylene, ether, dioxane, methanol, absolute ethanol oralso an excess of alkyl halide come into question. Generally the iodinecompounds are the most easy and chlorine compounds the most difiicult toreact. In the course of the reaction, quaternary ammonium iodides orbromides can be converted into the quaternary ammonium chlorides bymeans of silver chloride. Methyl iodide, methyl bromide, ethyl iodideand ethyl bromide are the most suitable alkyl halides. If necessary, thereactions can be performed in a pressure vessel.

When bis-primary diaminesare used as starting products, alkylation andquaternisation may be performed in the same process step.

The new bis-tertiary basesproducedaccording to this invention are liqiudsubstances capable of distillation in the vacuum without decomposition.The quaternary ammonium compounds are obtainedgenerally as colourlesscrystalised products when pure. They are soluble in water with an almostneutral reaction.

The compounds can be used as pharmaceuticals, e. g. to influence themuscle tonus. For instance, quaternary ammonium halides from1.10-bis-(aminoalkoxy) -decanes such as 1.10-bis- (B triethyl ammoniumethoxy) decane di-iodide or -dibromide have a strong muscle relaxingaction.

The following examples serve to illustrate the invention. Thetemperatures are in degrees centigrade and parts are always given asparts by weight in grammes.

Example 1 17.4 parts of 1.10-decane-diol, 30 parts of diethylaminoethylchloride and 8'7parts of abs. toluene are mixed and then heated to90-100.

8.2 parts of sodium amide finely ground with abs. toluene are then addedin small portions at this temperature, and the Whole mixture is stirredfor a further 2 hours at the same temperature, after which it is boiledfor 2 hours under reflux. After cooling, the base formed is convertedinto .the chlorhydrate solution by stirring with excess-(p-diethylamino-ethoxy) -decane is obtained as a colourless oil with aboiling point of 153-157 at 0.035 mm. pressure.

The same compound can also be obtained as follows: 17.4 parts of1.10-decane-diol, 50 parts of diethylamino-ethyl chloride and 160 partsof 50% caustic soda lye are stirred for 5 hours at 100". After dilutingthe bases so obtained in water, they are taken u in ether and thenconverted into the chlorhydrate solution by shaking the ether solutionwith Zn-hydrochloric acid. After extracting the aqueous chlorhydratesolution with ether, it is made alkaline with cone. causticsoda lye. Thebase which isprecipitated is taken up in ether and dried. The pure baseis obtained by fractional distillation of the ether extract.

Example 2 14 parts of the bis-tertiary base obtained according toExample 1 are warmed in a water bath at 50-60 for 14 hours with parts ofdry acetone and 19 parts of ethyl iodide. Filtration with suction isperformed after cooling and the 1.10-bis- (ii-triethyl ammonium ethoxy)-decane-di-iodide obtained is purified, if desired, by recrystallisationfrom butanone and a little abs. methanol. In this process the salt isdissolved in as little hot methanol as possible and then enough hotbutanone is added to cause a slight cloudiness. The solution is thencooled, filtered and the recrystallised product melts at 103.

The corresponding dibromide, which is produced by gently warming thebase with ethyl bromide in abs. ether, melts at 158.

Example 3 19.5 parts of dimethylamine-ethanol in 430 parts or abs.toluene are treated While stirring with a solution of 5 parts of sodiumin as little abs. methanol as possible. The methanol is then completelyfractionally distilled off. If necessary, the residue is increased toabout 200 parts by the addition of abs. toluene. A solution of 21.6parts of 1.4-dibromobutane in 174 parts of abs. toluene are then addeddropwise at boiling temperature over a period of 2 hours. The mixture isboiled for a further 6 hours under reflux and worked up as described inExample 1. L l-bis- (18-dimethylamino-ethoxy) -butane boils at 86- 89 at0.15 mm. pressure.

Example 4 20 parts of methyl iodide are added dropwise while stirring to11.6 parts of the base obtained according to Example 3 in 80 parts ofdry acetone while cooling with ice. When the violent reaction has beencompleted, the reaction mixture is warmed for some hours under refluxwhereupon the oily diquaternary ammonium iodide which precipitatestransforms into crystals. On recrystallisation from a mixture ofmethanol and butanone, the di-iodomethylate is obtained. M. P. 235".

Ezcample 5 24.4 parts of 1.6-dibromohexane and 38 parts ofa-diethylamino-butanol are heated to 50-60 in 100 parts of toluene. 10.5parts of sodium amide (finely ground in toluene) are slowly added atthis temperature while stirring. Stirring is continued for a further 2hours at 50-60 and thereafter for 24 hours at boiling temperature. Aftercooling, 2n hydrochloric acid is added carefully, the aqueouschlorhydrate solution is separated and extracted with ether. 30% ofcaustic soda lye is then added to the aqueous chlorhydrate solution, theoil which separates is taken up in ether and the ether solution is driedand distilled on. The bis-tertiary base, 1.6-bis-(5-diethylamino-butoxy)-hexane is obtained by fractional distillation in a high vacuum. Thecompound boils at 157-160 at 0.07 mm. pressure.

Examp la 6 p The corresponding diquaternary di-iodoethylate, 1. e.1.6-bis-(' -triethyl-ammonium-butoxy)- hexane di-iodide, is obtained byheating the bistertiary diamine described in example 5 with ethyl iodidein acetone. It melts at about 99 and is somewhat hygroscopic.

Example 7 20.4 parts of 1.4-di-(y-aminopropoxy)-butane are heated with45 parts of 35% formic acid and 80 parts of 37.2% aqueous formaldehydesolution for 14 hours at 95-100 while stirring. The starting product isobtained by catalytic hydrogenation of 1.4-di- (fi-cyanoethoxy) -butanewhich has been obtained by adding 2 mols of acrylonitrile to 1 mol of1.4-butane-diol). After cooling, 24 parts of conc. hydrochloric acid areadded and the Whole is evaporated to dryness in the vacuum. The residueis dissolved in water and on making the solution alkaline the base isprecipitated and after drying in ether it is purified by distillation inthe vacuum. 1.4-bis-( dimethylamino-propoxy) butane boils at 155- 159 at12 mm. pressure.

Example 8 If the base described in Example 7' is treated with a slightexcess of methyl iodide in acetone according to Example 4, thecorresponding diiodomethylate is obtained. M. P. 133.

Example 9 (Unsymmetrical compound) 34.8 parts of 1.10-decane-diol (0.2mol), 34.4 parts of diethylaminoethyl chloride-hydrochloride (0.2 mol)and 107 parts of 50% caustic soda lye are stirred together for 6 hoursat 100. After cooling, the mixture is diluted with a little water,ethered out and the bases are transferred into the chlorhydrate solutionby shaking the ether solution with 2n hydrochloric acid. Thechlorhydrate solution is extensively extracted with ether and then madealkaline. The bases which are precipitated are then taken up in ether,dried with potassium carbonate and fractionally distilled. The monoetherIO-(B-diethylamino-ethoxy)-decanol-(l) is obtained at a boiling point ofl30-132 at 0.03 mm. pressure. The diether1.10-bis(fi-diethylamino-ethoxy)-decane is ob-i tained as a by-product.This passes over at 155 at 0.03 mm. pressure.

3 parts of sodium amide (finely ground and suspended in toluene) areadded in small portions to 13.2 parts of lo-(s-diethylamino-ethoxy)-decanol-( 1) and 8 parts of y-dimethylamino-propyl chloride in 50 partsof abs. toluene at 60-70 while stirring. The whole is kept at 60-70 for2 hours and then boiled for a further 24 hours. After cooling,2n-hydrochloric acid is added carefully, the aqueous chlorhydratesolution is separated, made alkaline and the base which is precipitatedis ethered out. The ether solution is dried and the ether is distilledoff. 1(fl-diethylamino-ethoxy) -10('y dimethylamino-propoxy) -decane isobtained by distillation in the high vacuum. B. P. 144-149 at 0.03 mm.pressure.

Di-iodomethylate is obtained by warming with methyl iodide in acetone.

Ewample 10 9.5 parts of sodium amide (finely ground and suspended intoluene) are added to 34.8 parts of 1.10-decane-diol (0.2 mol) 30 partsof 'y-diethylamino-propyl chloride (0.2 mol) in parts of toluene at50-60 while stirring. The whole is then held at 50-60 for 2 hours andthen boiled for 24 hours. The basic end product is isolated in the usualway, and purified by fractional distillation. 10 diethylamino propoxy)decanol-(l) is obtained. B. P. -141 at 0.045 mm. pressure.

This base is converted into l-(B-dimethylamino-ethoxy) -10-(vdiethylamino propoxy) -decane by reaction with dimethylamino-ethylchloride and sodium amide in toluene. B. P. 153158 at 0.07 mm. pressure.

Di-iodomethylate is obtained by warming with methyl iodide in acetone.

The following bis-tertiary amines and quaternary ammonium compounds forexample can be produced in the manner described above:

1. 1.2-bis- -dimethylamino propoxy) ethane, B. P. (10 mm.) 139-144.Di-iodornethylate, M. P. 175.

2. 1.3-bis- -dimethylamino propoxy) -propane, B. P. (10 mm.) 155-161.Di-iodomethylate, M. P. 171. 1

3. 1.4 bis ([3 diethylamino ethoxy) -butane, B. P. (0.07 mm.) 108.Di-iodoethylate, M. P. 184.

4. 1.4-bis(;8 piperidino ethoxy)-butane,' B. P. (0.4 mm.) 163-164.Di-iodomethylate, M. P. 204. Di-idoethylate, M. P. 150-153.

5. 1.4-bis-(v diethylamino propoxy) butane,

' B. P. (0.03 mm.) 117-118". Di-iodoethylate, M. P.--148. i

6. 1.4-bis(o-dimethylamino-butoxy) -butane, B. P. (0.1 mm.) 128-131.Di-iodornethylate, M. P. 2l2-213.

7. 1.5-bis (,3 dimethylamino-ethoxy) pentane, B. P. (0.2 mm.) 103-105".Di-iodomethylate, M. P. 145-146.

8. 1.5 bis 8 diethylamino ethoxy)-pentane, B. P. (0.09 mm.) 119-121.Di-iodoethylate, M. P. 121-124.

9. 1.6 bis (,6 dimethylamino-ethoxy) -hexane, B. P. (12 mm.) 162-184".Di-iodomethylate, M. P. 132.

10. 1.6 bis (,e diethylamino ethoxy) -hexane,

- B. P. (0.02 mm.) 110-112. Di-iodoethylate;

M. P. ll9-120.

11. 1.6; bis (B morpholino ethoxy) hexane, B. P. (0.3 mm.) 203-204.Di-iodomethylate,

12. 1.6 bis ('y dimethylamino-propoxy) -,hex-

ane,B.'P. (0.08 mm.) 119-123. Di-iodomethylate, M. P. 207-209".

13. .1.6-bis( diethylamino property) hexane B. P. (0.03 mm.) 133-135".Di-ioclomethylate, hygroscopic. Di-iocloethylate, hygroscopic.

14. 1.6 bis ('y dibutylamino propoxy) -heX- ane B. P. (0.04 mm.)192-195. Di-iodoethylateyM. P. 126-128.

15. 1.6 bis (a dimethylamino butoxy) -hex- 39. 1.6 bis (6- [2 methylpiperidino'lethoXy)-hexane. Di-iodomethylate.

40. 1.6 bis (6 morpholino butoxy) Di-ioclomethylate.

41. 1.10 bis pyrrolidino-propoxy) decane.

Di-bromethylate.

42. 1.12 bis 8 pyrrolidino ethoxy) ddecane. Di-iodethylate.

43. 1.16 bis ([3 piperidino ethoxy) hexane.

hexaane, B. P. (0.08 mm.) 136-138". Di-iodometh- 10 decane.Di-iodomethylate.

ylate, M. P. 180-183. Wh at I claim 1s. 46221334'P it ifi i iiiiii? 21553.322 A compound of the general formula methylate, M. P. 160-161.

1'7. 1.7 bis (,8 dimethylamino ethoxy) hep- Am-(CHz)mO-(CHz)nO(CH2)m'Amtane, B. P. (0.05 mm.) 133-141. Di-iodometh- Ha} ylate, M. P. 142-145.

18' 133M345 dimethylamino eulogy) fictane wherein Am represents a memberselected from B P (005 1424446 Diqodomethvlate, the group consisting ofdialkylamino radicals M- 20 wherein each alkyl group contains from 1-4carbis (fi diethylammg ethoxy) octane, bcn atoms, the morpholino radicaland 5- and YB P (0037mm) 1564530. nidodoethylate 6-sided polymethyleneimino radicals containing from 4 to 6 carbon atoms, R represents an 20.1.8 bis (,y diethy1ammO prepoxy) oatane, alkyl radical containing from 1to 4 carbon at- (005 1634650 niqodoethylate, oms, Hal represents ahalogen atom of a molec- P ular weight of at least 35, m and m represent2] L9 bis (B dimethylamino ethoxy) integers from 2 to 4, and nrepresents an integer ane, B. P. (0.00 mm.) mas-150. Di-iodomethfrom 4to ylate, 311-04113 2. A compound of the general formula:

22.1.9 bis (6 diethylamino ethoxy)- R\ /R nonane, B. P. (0.06 mm.)154-159. Di-iodomic112)m-o-(ormm-o-(onom -Am ethylate, M. P. 123-125".

23. 7.10 bis (6 dimethylamino ethoXy)- Hal Hal decane, B. P. (0.04 mm.)134-13'7. Di-iodowherein Am represents 6-Sided p y methylate, M. P. 151.Di-iodoethylate, ylene imino radical containing from-4 to 6 car- M. P.95. Di-bromobutylate, M. P. 148-149. 10010 atoms, R represents an alkylr l on- 24, 1,10 bi (p piperidino ethoxy) d a e, taming from 1 to 4carbon atoms, Hal represents B, P. (0.04 mm 159463", Di-iodoethylate, ahalogen atom of a molecular weight of at least M, P 112 35 and m and mrepresent integers from 2 to 4.

25. 1.10 bis (p morpholino ethoxy) decane, 4U A mp f the g n ral frmula:

B. P. (0.15 mm.) 211-215. Di-iodoethylate, R R M. P. 102.

26. 1.10 bis dimethylamino propoxy)- AmCH2OH2-O(CHW'OFCHFCHPAUI decaneB. P. (0.02 mm.) 140-144. Di-iodo- H01 Hal methylate, M. P. 148-150".415 wherein Am represents a 5- to 6-sided poly- 27. 1.10 bis (vdiethylamino propoxy)- methylene imino radical containing from 4 to 6decane, B. P. (0.03 mm.) 164-169". Di-iodocarbon atoms, R represents analkyl radical conethylate, M. P. 90-91. taining from 1 to 4 carbon atomsand Hal repre- 28. 1.10 bis (v dibutylamino propoxy)- sents a halogenatom of a molecular weight of decane, B. P. (0.09 mm.) 230-231.Di-iodoat least 35. ethylateyM. P. 86. 4. A compound of the formula:

9- 11 s l dimethylamino y) 5. A compound of the general formula:

decane. Di-iodomethylate. R R

31. 1.14 bis (/3 diethylamino ethoxy) tet- Hal H radecane.Di-iodoethylate.

. wherein Am represents a dialkylammo radical bls dlmethylammo butoxy)"wherein each alkyl group contains from 1 to 4 pentadecane.Di-chloromethylate. arbon atoms R nt 1k 1 33. 1.10 bis (,a dimethylaminoethoxy)- c eprese 8 ma y m hexadecane th late tamlng from 1 to 4 carbonatoms, Hal represents 34 1 l6 bi 1 g Minn r X a halogen atom of amolecular weight of at h g 'iodomethsglate 0 p 0pc y least '35 and m andm represent integers from i tii g bfi g fifi fggfi ethoxy) 6, A compoundof the general formula:

36. 1.20 bis 8 dimethylamino ethoxy)- eicosane. Di-ioclomethylate.OHZ)1O O OHZ CHPAH,

37. 1.4 bls (.6 pyrrolidmo ethoxy) butane. H 1 Di-chlorethylate. a 38.1.6 bis ('y pyrrolidino propoxy) hexwherein Am represents a dialkylaminoradical -.ane. .Di-iodomethylate. wherein each alkyl group contains from1 to 4 9 carbon atoms, R represents an alkyl radical containing from 1to 4 carbon atoms, and Hal represents a halogen atom of a molecularweight of at least 35.

7. A compound of the general formula:

CH3 Hal Ha l CHa wherein R represents an alkyl radical containing from 1to 4 carbon atoms and Hal represents a halogen atom of a molecularweight of at least 35.

8. A compound of the formula:

Number Number UNITED STATES PATENTS Name Date Callsen Dec. 9, 1924Ulrich et a1. Nov. 22, 1938 Ulrich et a1 Sept. 12, 1939 Reynolds et a1Aug. 11, 1942 Gresham Oct. 22, 1946 Dickey et a1 Dec. 10, 1946 Ballardet al Feb. 21, 1950 Fourneau Mar. 6, 1951 De Benneville July 10, 1951FOREIGN PATENTS Country Date France Mar. 5, 1943

1. A COMPOUND OF THE GENERAL FORMULA: